Project Summary?Drug Discovery and Structural Biology Shared Resource The Drug Discovery and Structural Biology Shared Resource (DDSB) is a new Mays Cancer Center (MCC)- supported Shared Resource that combines comprehensive services to better meet the needs of MCC users. The purpose of the DDSB is to provide state-of-the-art capabilities to MCC investigators for the study of cancer- related macromolecules at the atomic and molecular levels, how they interact with other macromolecules such as ligands, and for identification of small molecules that can target them using advanced tools such as X-ray crystallography, nuclear magnetic (NMR) and surface plasmon resonance (SPR), and high-throughput screening (HTS) technologies ? including, but not limited to, cell-based phenotypic high-content imaging-based and purified component-based HTS. The DDSB makes critical contributions to the MCC?s overarching mission to end cancer by providing a comprehensive platform that integrates structural biology, molecular phenotypes, and drug discovery to expand knowledge on the etiology of cancer, discover cancer-relevant targets, and identify potential therapeutics. The DDSB is composed of four integrated modules: (a) Small Molecule Probe and Drug Discovery, (b) NMR, (c) X-ray Crystallography, and (d) Macromolecular Interactions. Each module is led by an expert in that field, with oversight of all modules provided by Matthew Hart, Ph.D. Depending on the project, DDSB can perform focused studies involving one or more modules, or perform integrative studies involving all modules. During the last reporting period (2014-2018), the DDSB worked with 40 MCC members who used 53% of total service time. In this period, the DDSB supported 20 cancer-related publications. DDSB activities also generated a pipeline of 10 lead compounds in the structure-guided optimization stage and 18 early-stage projects, ~50% of which are expected to reach lead optimization within two years. At the end of the next funding period we expect to have delivered 5-8 new vetted leads, ready to move into preclinical stages, to cancer investigators. To further its goals, the DDSB will establish advanced novel tools for X-ray crystallography, high-throughput screening (including approaches that target heretofore ?undruggable? targets), and directed cancer-related target degradation. During the next funding period, we expect the DDSB to continue advancing our understanding of mechanisms that drive cancers and identifying novel cancer therapeutics to be tested for future clinical use. The DDSB unites multiple capabilities challenging for individual investigators to pursue because of the cost, required maintenance of the instrumentation, and breadth of expertise needed to use these technologies. Thus, the DDSB is essential for the MCC to achieve its strategic goal of translating a molecular understanding of the processes that underlie cancer into novel therapies.